Physical Activity, Obesity, and Subclinical Myocardial Damage

JACC: HEART FAILURE

VOL. 5, NO. 5, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jchf.2017.02.002

Physical Activity, Obesity, and Subclinical Myocardial Damage Roberta Florido, MD,a Chiadi E. Ndumele, MD, MHS,a,b Lucia Kwak, MS,b Yuanjie Pang, SCM,b Kunihiro Matsushita, MD, PHD,b Jennifer A. Schrack, PHD,b Mariana Lazo, MD, PHD,b,c Vijay Nambi, MD, PHD,d,e Roger S. Blumenthal, MD,a Aaron R. Folsom, MD, MPH,f Josef Coresh, MD, PHD,b Christie M. Ballantyne, MD,e Elizabeth Selvin, PHD, MPHb

ABSTRACT OBJECTIVES This study sought to evaluate the association of physical activity with chronic myocardial damage, assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT), in individuals with and without obesity. BACKGROUND Physical activity is associated with reduced risk of heart failure (HF), particularly among obese people. The role of chronic myocardial damage in this association is uncertain. METHODS We studied 9,427 participants in the Atherosclerosis Risk in Communities Study without cardiovascular disease, with body mass index >18.5 kg/m2. Physical activity was categorized per American Heart Association guidelines as recommended, intermediate, or poor. We evaluated cross-sectional associations of physical activity and obesity with elevated hs-cTnT ($14 ng/l). In prospective analyses, we quantified the association of elevated hs-cTnT with HF risk within cross-categories of baseline physical activity and obesity. RESULTS People with poor physical activity were more likely to have elevated hs-cTnT than those with recommended levels (odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.15 to 1.68). In cross-categories of physical activity and obesity, using the non-obese/recommended activity group as the reference, individuals with obesity and poor activity were most likely to have elevated hs-cTnT (OR: 2.46; 95% CI: 1.91 to 3.19), whereas the obese/recommended activity group had a weaker association (OR: 1.68; 95% CI: 1.28 to 2.21; p < 0.001 for interaction between physical activity and obesity). In prospective analyses, elevated hs-cTnT was strongly associated (p < 0.001) with incident HF in all obesity/ physical activity cross-categories (p > 0.20 for interaction). CONCLUSIONS Physical activity is inversely associated with chronic subclinical myocardial damage. Physical activity might lessen the association between obesity and subclinical myocardial damage, which could represent a mechanism by which physical activity reduces HF risk. (J Am Coll Cardiol HF 2017;5:377–84) © 2017 by the American College of Cardiology Foundation.

From the aJohns Hopkins Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland; bDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; c

Department of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; dMichael E.

DeBakey Veterans Affairs Hospital, Houston, Texas; eDivision of Atherosclerosis and Vascular Medicine, Baylor College of Medicine, and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas; and the f

Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota. The

views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. ARIC is conducted as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C,

HHSN268201100006C,

HHSN268201100007C,

HHSN268201100008C,

HHSN268201100009C,

HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). This work was supported by a Robert Wood Johnson Amos Medical Faculty Development Award and a National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute grant (K23HL12247) awarded to Dr. Ndumele and by an NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant (R01DK089174) awarded to Dr. Selvin. Dr. Selvin was also supported by NIH/NIDDK grant K24DK106414. Dr. Schrack is a consultant for EMD Serono Research & Development Institute, Inc. Dr. Nambi has served as an event adjudicator for a study sponsored by Siemens to evaluate a new high-sensitivity troponin assay. Drs. Selvin and Ballantyne have served on an advisory board for Roche Diagnostics. Drs. Ballantyne and Nambi, along with Roche and Baylor College of Medicine, have filed a provisional patent (patent #61721475) entitled “Biomarkers to Improve Prediction of Heart Failure Risk.” All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received October 21, 2016; revised manuscript received February 1, 2017, accepted February 1, 2017.

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Physical Activity, Obesity, and hs-cTnT

P

ABBREVIATIONS

hysical activity is widely appreciated

visits that occurred approximately every 3 years, and

as a key component of strategies to

at a fifth visit conducted from 2011 to 2013. Physical

reduce risk of heart failure (HF) (1).

activity was assessed in all participants at visit 3 (1993

Physical activity has been linked to a lower

to 1995), whereas measurements of hs-cTnT were ob-

likelihood of HF among people with obesity, a

tained for all participants at visit 4 (1996 to 1998). We

group at particularly elevated risk of HF (2,3).

therefore performed nonconcurrent cross-sectional

Notably, the reduced HF risk associated with

analyses evaluating the associations of physical

physical activity among people with obesity is

activity and obesity status at visit 3 with prevalent

not fully explained by traditional risk factors

hs-cTnT levels at visit 4. In prospective analyses, we

for cardiovascular disease (CVD), which sug-

additionally assessed the risk of incident HF associ-

HR = hazard ratio

gests the protective association of physical

ated with elevated hs-cTnT within cross-categories of

hs-CRP = high-sensitivity

activity against HF might be mediated in part

physical activity and obesity.

AND ACRONYMS BMI = body mass index CI = confidence interval CVD = cardiovascular disease eGFR = estimated glomerular filtration rate

HDL = high-density lipoprotein HF = heart failure

C-reactive protein

through nontraditional mechanisms.

hs-cTnT = high-sensitivity

Of 12,887 individuals who attended visit 3, a total with

of 9,427 were eligible for this study. We excluded

abnormalities of myocardial structure and

individuals for whom data were missing on physical

function and subsequent HF (4) via unclear

activity or body mass index (BMI) at visit 3 (n ¼ 40)

pathways (5). An increasingly appreciated

or on hs-cTnT at visit 4 (n ¼ 1,796); those with self-

pro–B-type natriuretic peptide

risk factor for the development of HF is

reported CVD, a CVD clinical event (HF or coronary

OR = odds ratio

subclinical myocardial damage, as reflected

heart disease, including coronary revascularization

by levels of cardiac troponin T measured with

procedures), or silent myocardial infarction at or

novel high-sensitivity assays (hs-cTnT) (6,7).

before visit 4 (n ¼ 1,492); those not of black or white

Obesity

cardiac troponin T

METs = metabolic equivalents of task

NT-proBNP = N-terminal

SBP = systolic blood pressure

has

potent

associations

CVD,

race (n ¼ 38); and those with a BMI <18.5 kg/m 2

obesity has been independently linked to elevated hs-

(n ¼ 94). All participants provided informed consent,

cTnT levels, and the combination of obesity and

and the study protocol was approved by the institu-

elevated

tional review boards at each study site.

Indeed,

among

individuals

hs-cTnT

is

without

associated

prior

with

markedly

increased HF risk (8). It is presently unknown whether higher physical activity is associated with

MEASUREMENT OF STUDY VARIABLES. The primary

lower levels of subclinical myocardial damage in the

exposure was physical activity, measured through a

presence or absence of obesity. Decreased myocardial

modified Baecke questionnaire (10) at visit 3 (1993 to

damage could represent a pathway by which physical

1995). The questionnaire asked questions on partici-

activity is related to lower HF risk.

pation in up to 4 sports or exercise physical activity within the previous year and the number of hours per

SEE PAGE 385

We therefore tested the hypothesis that physical activity has an inverse association with elevated hs-cTnT in a community-based population of men and women without clinical CVD and that higher physical activity lessens the association between obesity and subclinical myocardial damage. To evaluate the clinical importance of these associations, we also assessed the link between elevated hs-cTnT and subsequent HF risk within groups defined by physical activity and obesity status.

METHODS

week and months per year spent on each sport. As has been done in prior ARIC analyses (11,12), we converted the Baecke sports indices into minutes per week of moderate or vigorous exercise. Each activity was converted into metabolic equivalents of task (METs) based on the Compendium of Physical Activities. Moderate activities were defined as those involving a workload of 3 to 6 METs, and vigorous activities were those involving a workload of >6 METs. We subsequently categorized physical activity according to the American Heart Association guidelines as recommended ($75 min/week of vigorous intensity or $150 min/week of any combination of moderate and vigorous intensity), intermediate (1 to 74 min/week of

STUDY POPULATION. The ARIC (Atherosclerosis Risk

vigorous intensity or 1 to 149 min/week of any com-

In Community) study is a multicenter, prospective,

bination of moderate and vigorous intensity), or poor

observational cohort investigation of CVD and related

(0 min/week of moderate or vigorous exercise) (13).

conditions in middle-aged men and women. The study

We also modeled physical activity as a continuous

design has been described previously (9). Briefly, a

variable in MET  min/week and used this continuous

total of 15,792 people age 45 to 64 years were enrolled

variable to generate quartiles of physical activity.

between 1987 and 1989 from 4 US communities. Par-

BMI was calculated from measured height and

ticipants were examined at baseline, at 3 subsequent

weight at visit 3 and categorized as non-obese

Florido et al.

JACC: HEART FAILURE VOL. 5, NO. 5, 2017 MAY 2017:377–84

Physical Activity, Obesity, and hs-cTnT

(BMI 18.5 to <30 kg/m 2) or obese (BMI $30 kg/m2 ).

We used the highest (“recommended”) physical ac-

Information on additional covariates of interest was

tivity category (individuals performing $75 min/week

obtained through history, physical examination, and

of vigorous-intensity activity or $150 min/week of

laboratory data at visit 3. Smoking status was cate-

any combination of moderate- and vigorous-intensity

gorized as current or noncurrent smoker, and alcohol

exercise physical activity) as the reference group. We

consumption was quantified in grams per week. Dia-

constructed 2 models, one with confounders and a

betes mellitus was defined as fasting glucose $126

second that also included potential mediators of the

mg/dl, nonfasting glucose $200 mg/dl, self-reported

effects of physical activity on subclinical myocardial

history of diabetes mellitus, or use of hypoglycemic

damage. Model 1 included age, sex, race, smoking

agents. Systolic blood pressure (SBP) was measured 3

status, and alcohol intake. Model 2 included all vari-

times, and the mean of the second and third mea-

ables from model 1 plus SBP, antihypertensive medi-

surements was used for analyses.

cation use, diabetes mellitus, total cholesterol, HDL

Total cholesterol, high-density lipoprotein (HDL)

cholesterol, and triglycerides. We constructed a third

cholesterol, and triglycerides were measured with

adjustment model that included the variables in

standardized

function

model 2 and additional predictors of future HF, such

was assessed by use of the estimated glomerular

as heart rate, eGFR, NT-proBNP, and hs-CRP. Cova-

filtration rate (eGFR) calculated based on serum

riates were selected a priori based on previously

creatinine at visit 4 using the Chronic Kidney

published data and known risk factors for HF.

Disease Epidemiology Collaboration (CKD-EPI) equa-

We conducted sensitivity analyses with physical ac-

tion (14). N-terminal pro–B-type natriuretic peptide

tivity modeled as quartiles. We additionally evaluated

(NT-proBNP) and high-sensitivity C-reactive protein

the continuous association of physical activity (in

(hs-CRP) were measured from plasma collected at

MET  min/week) with elevated hs-cTnT by scaling

visit 4 and frozen at 80 C.

per 1 SD and constructing restricted cubic spline

enzymatic

assays.

Renal

The primary outcome in cross-sectional analyses

models. We tested for multiplicative interactions with

was elevated hs-cTnT, defined as a level $14 ng/l, a

age ($ or <65 years), race, and sex on the association

cutpoint that has been used in several prior analyses

between physical activity and hs-cTnT.

(6,7). Hs-cTnT levels were measured in 2011 from visit

To evaluate the association between physical activity

4 plasma samples that had been stored at 80 C,

and hs-cTnT in the presence and absence of obesity, we

using a high-sensitivity assay (Elecsys troponin T,

conducted analyses stratified by obesity status (non-

Roche

As

obese and obese) using regression models that included

reported previously, the reliability coefficient for

the same covariates outlined above. We also created

hs-cTnT measurements among the ARIC study par-

cross-categories of physical activity (recommended,

ticipants was 0.94 (15). The between-assay coefficient

intermediate, poor) and obesity status (non-obese,

of variation for control materials was 6.9% for mean

obese) to assess the combined association of these 2

hs-cTnT concentrations of 29 ng/l.

exposure variables with elevated hs-cTnT, using a

Diagnostics,

Indianapolis,

Indiana).

INCIDENT HF. In prospective analyses, the outcome

of interest was incident HF, defined as the first hospitalization or death related to HF. HF deaths were identified by hospital discharge codes and death certificates,

with

International

Classification

of

Diseases-9th Revision code 428 used to identify hospitalizations and deaths early in follow-up and International Classification of Diseases-10th Revision code I-50 used for HF deaths in later follow-up. Information on hospitalizations was obtained from participants via yearly telephone calls, and vital records were examined for all deaths. HF events occurring

from

2005

onward

were

additionally

adjudicated by an expert panel (16). STATISTICAL

ANALYSIS. We

used

common reference group of non-obese individuals with recommended physical activity. We performed additional analyses using abdominal obesity, defined by World

Health

Organization

criteria

as

a

waist

circumference $88 cm for women and $102 cm for men, as an alternative measure of adiposity. In prospective analyses, the baseline was ARIC visit 4 (the time point of hs-cTnT measurement), with follow-up for incident HF through December 31, 2012. We constructed Poisson and Cox proportional hazards regression models, with adjustment for covariates at visit 3, to estimate the adjusted incidence rates and hazard ratios (HRs) with associated 95% confidence intervals (CIs) for incident HF within each crosscategory of physical activity and obesity. To eval-

multivariable

uate the clinical implications of the associations of

logistic regression models to evaluate the adjusted

physical activity and obesity with elevated hs-cTnT,

associations of physical activity categories with

we then constructed regression models to estimate

myocardial damage, as assessed by elevated hs-cTnT.

the incidence rates and HRs for HF associated with

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Physical Activity, Obesity, and hs-cTnT

T A B L E 1 Characteristics of Study Population According to Physical Activity Categories at

Baseline: The ARIC Study (1993 to 1995)

Physical activity categories were fairly evenly distributed across the study population, with 43% of individuals reporting recommended, 23% intermediate,

Physical Activity Category

and 34% poor levels of physical activity. Among those

Recommended (n ¼ 4,043) (43%)

Intermediate (n ¼ 2,178) (23%)

Poor (n ¼ 3,206) (34%)

p Value

performed recommended levels of physical activity.

60.6  5.8

60.0  5.6

59.6  5.5

<0.0001

Compared with those with recommended physical

Female, %

51.8

65.0

60.5

<0.0001

activity, participants with lower levels of physical ac-

African American, %

15.2

20.8

28.6

<0.0001

12.5

14.6

21.0

<0.0001

tivity were more likely to be women, African-

Current smoker, %

42.0 (90.7)

37.4 (94.8)

37.9 (116.0)

Age, yrs

Alcohol intake, g/week

with and without obesity, 33% and 47%, respectively,

0.13

Americans, and current smokers and had higher SBP, prevalence of diabetes, and BMI. Lower physical ac-

29.1

31.4

34.9

<0.0001

SBP, mm Hg

122.3  17.5

123.2  18.4

125.1  19.0

<0.0001

Diabetes, %

10.2

13.0

15.1

<0.0001

levels and higher heart rate, eGFR, and hs-CRP. There

HDL cholesterol, mg/dl

53.7  18.4

54.2  18.7

51.7  17.0

<0.0001

were no significant differences in NT-proBNP levels

Total cholesterol, mg/dl

207.2  37.0

209.4  37.1

207.5  37.4

0.06

Triglycerides, mg/dl

137.4  93.9

139.5  78.9

141.3  83.5

0.16

27.5  4.6

28.5  5.1

29.4  6.0

<0.0001

Antihypertensive medications, %

BMI, kg/m2 Heart rate, beats per min

64.2  9.5

66.0  9.6

66.4  9.8

<0.0001

eGFR, ml/min/1.73 m2

85.7  14.5

86.6  15.8

87.9  16.5

<0.0001

155.5  3019.2

128.3  532.0

113.9  368.0

0.67

3.7  6.0

4.2  5.7

5.2  7.5

<0.0001

NT-proBNP, pg/ml hs-CRP, mg/l

tivity was also associated with lower HDL cholesterol

across categories of physical activity. Within the study population, 7.2% of individuals had elevated hs-cTnT levels. The prevalence of elevated hs-cTnT increased with lower physical activity levels, being found among 6.8%, 7.0%, and 7.7% of individuals with recommended, intermediate, and poor activity levels, respectively.

Values are mean  SD, or n (%). Physical activity categories defined as follows: poor (0 min/week moderate or vigorous), intermediate (1 to 74 min/week of vigorous or 1 to 149 min/week of moderate and vigorous), and recommended ($75 min/week of vigorous or $150 min/week of moderate and vigorous). BMI ¼ body mass index; eGFR ¼ estimated glomerular filtration rate; HDL ¼ high-density lipoprotein; hs-CRP ¼ high-sensitivity C-reactive protein; hs-cTnT ¼ high-sensitivity cardiac troponin T; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; SBP ¼ systolic blood pressure.

In logistic regression analyses, lower categories of physical activity were associated with significantly higher odds of subclinical myocardial damage. Relative to those with recommended physical activity levels, people with poor physical activity were more

elevated hs-cTnT within each of the cross-categories of physical activity and obesity status. We created an interaction term and performed likelihood ratio tests to test for heterogeneity in the associations between elevated hs-cTnT and incident HF across the cross-categories. Statistical analyses were performed with Stata version 13.1. All p values presented are 2-sided.

RESULTS

likely to have elevated hs-cTnT (odds ratio [OR]: 1.39; 95% CI: 1.15 to 1.68) after adjustment for confounders (Table 2). Notably, a significant inverse association between physical activity and elevated hs-cTnT remained after additional adjustment for several potential CVD mediators (OR: 1.31; 95% CI: 1.08 to 1.59) (Table 2). We noted similar trends, although of only borderline statistical significance, after additional adjustment for heart rate, eGFR, NT-proBNP, and hsCRP (OR: 1.21; 95% CI: 0.99 to 1.49) (Table 2). When physical activity was modeled continuously, its as-

Characteristics of the study population according to

sociation with elevated hs-cTnT remained significant

physical activity categories are presented in Table 1.

(p ¼ 0.02). In analyses that modeled physical activity as quartiles, we observed a significant association between lower physical activity quartiles and a higher

T A B L E 2 ORs (95% CIs) for Elevated hs-cTnT Associated With

likelihood of myocardial damage (Figure 1A). A graded

Lower Physical Activity Categories

association between lower levels of physical activity and higher odds of subclinical myocardial damage

Physical Activity Category Recommended (n ¼ 4,043)

Intermediate (n ¼ 2,178)

Poor (n ¼ 3,206)

p Value for Trend*

Model 1

Ref. (1)

1.34† (1.08–1.66)

1.39† (1.15–1.68)

<0.001

Model 2

Ref. (1)

1.25 (1.00–1.57)

1.31† (1.08–1.59)

0.001

Model 3

Ref. (1)

1.15 (0.91–1.45)

1.21 (0.99–1.49)

0.02

Model 1: adjusted for age, race, sex, smoking status, and alcohol use. Model 2: adjusted for model 1 plus SBP, antihypertensive medication use, diabetes, total cholesterol, HDL cholesterol, and triglycerides. Model 3: adjusted for model 2 plus heart rate, eGFR, NT-proBNP, and hs-CRP. *Calculated using continuous physical activity, in METs (metabolic equivalents of task)  min per week. †Statistically significant. CI ¼ confidence interval; hs-cTnT ¼ high-sensitivity cardiac troponin T; OR ¼ odds ratio.

was also demonstrated in restricted cubic spline models (Figure 1B). Results were similar across age, race, and sex subgroups, with no significant interaction between physical activity and these demographic variables on the outcome of elevated hs-cTnT. We found similar results in analyses stratified by obesity status. A significant inverse relationship was observed between physical activity modeled continuously and elevated hs-cTnT among both obese (p ¼ 0.01) and non-obese (p ¼ 0.02) participants.

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Physical Activity, Obesity, and hs-cTnT

F I G U R E 1 Association of Physical Activity With Elevated High-Sensitivity Cardiac Troponin T

(A) Association of quartiles of physical activity with odds ratios and 95% confidence intervals (CI) for elevated high-sensitivity cardiac troponin T. Reference: Quartile 4: $1,365.9 MET  min/week. Adjusted for age, race, sex, smoking status, and alcohol use. Cutpoints for quartiles of physical activity: Quartile 1: 0 to 453.6 MET  min/week; quartile 2: 453.6 to 846.3 MET  min/week; quartile 3: 846.3 to 1364.9 MET  min/week; and quartile 4: $1,365.9 MET  min/week. (B) Continuous association between physical activity and elevated high-sensitivity cardiac troponin T among participants without clinical cardiovascular disease in restricted cubic spline models. Reference: 95th percentile, 2,182 MET  min/week. *Adjusted for age, race, sex, smoking status, and alcohol use. MET ¼ metabolic equivalents of task.

Each 1-SD lower physical activity level (781 MET 

obesity status. Over a median 15 years of follow-up,

min/week) was significantly associated with a higher

there were 1,178 HF events in the study population.

likelihood of elevated hs-cTnT both in people who

As shown in Online Table 2, the adjusted incidence rate

were obese (OR: 1.22; 95% CI: 1.05 to 1.42) and those

for HF (per thousand person-years) was lowest in the

who were non-obese (OR: 1.14; 95% CI: 1.02 to 1.27).

subgroup who were not obese and who had recom-

In analyses evaluating the association of cross-

mended activity levels (5.75), whereas the highest

categories of physical activity and obesity status

rates were seen in the obese and poor activity subgroup

with elevated hs-cTnT after adjustment for con-

(14.09). A similar pattern was seen in Cox regression

founders (Table 3), using the non-obese and recommended activity group as the reference, we found that individuals in the obese and poor physical ac-

T A B L E 3 Adjusted ORs* (95% CIs) for Elevated hs-cTnT According to Cross-Categories of

tivity group were most likely to have elevated

Physical Activity and Obesity Status at Baseline

hs-cTnT (OR: 2.46; 95% CI: 1.91 to 3.19). However, the combination of obesity and recommended physical activity levels had a weaker association with elevated hs-cTnT (OR: 1.68; 95% CI: 1.28 to 2.21). After further adjustment for CVD mediators (Table 3), the combi-

elevated hs-cTnT (OR: 1.20; 95% CI: 0.90 to 1.61). Similar trends were noted after additional adjustment for

heart

rate,

eGFR,

NT-proBNP,

and

Non-obese Obese

tion between physical activity and obesity on the outcomes of hs-cTnT was seen in all models. Analogous patterns were seen when waist circumference, categorized with World Health Organization criteria for abdominal obesity, was used as an alternative metric for adiposity (Online Table 1). In prospective analyses, we evaluated the association between elevated hs-cTnT and subsequent HF risk within each cross-category of physical activity and

Poor

1.00 (Ref. (1)) n ¼ 3,043

1.22 (0.92–1.62) n ¼ 1,459

1.20 (0.93–1.54) n ¼ 1,935

0.02

1.68‡ (1.28–2.21) 2.37‡ (1.74–3.23) 2.46‡ (1.91–3.19) n ¼ 1,000 n ¼ 719 n ¼ 1,271

0.01

<0.001

Model 2 Non-obese Obese

hs-CRP

(Table 3). Notably, a statistically significant interac-

Intermediate

Model 1

nation of obesity and recommended physical activity levels was no longer significantly associated with

p Value for p Value for Trend* Interaction†

Recommended

1.00 (Ref. (1)) n ¼ 3,043

1.17 (0.88–1.55) n ¼ 1,459

1.18 (0.91–1.52) n ¼ 1,935

0.03

1.20 (0.90–1.61) 1.66‡ (1.20–2.29) 1.73‡ (1.32–2.27) n ¼ 1,000 n ¼ 719 n ¼ 1,271

0.01

0.011

Model 3 Non-obese Obese

1.00 (Ref. (1)) n ¼ 3,043

0.99 (0.73–1.34) n ¼ 1,459

1.03 (0.79–1.35) n ¼ 1,935

0.32

1.11 (0.81–1.49) n ¼ 1,000

1.56‡ (1.11–2.18) n ¼ 719

1.63‡ (1.23–2.15) n ¼ 1,271

0.01

0.003

Using a common reference group of non-obese with poor physical activity. Non-obese: BMI 18.5 to <30 kg/m2; obese: $30 kg/m2. Model 1: adjusted for age, race, sex, smoking status, and alcohol use. Model 2: adjusted for model 1 variables plus SBP, antihypertensive medication use, diabetes, total cholesterol, HDL cholesterol, and triglycerides. Model 3: adjusted for model 2 plus heart rate, eGFR, NT-proBNP, and hs-CRP. *Calculated with continuous physical activity, in MET  min/week. †Interaction term across cross-categories calculated with likelihood ratio tests. ‡Statistically significant. Abbreviations as in Tables 1 and 2.

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Physical Activity, Obesity, and hs-cTnT

cross-categories of physical activity and obesity sta-

F I G U R E 2 Adjusted Incidence Rates for Incident HF Associated With Elevated and

tus, those with recommended physical activity levels

Nonelevated hs-cTnT Within Each Cross-Category of Physical Activity and

and without obesity had the lowest likelihood of

Obesity Status

subclinical myocardial damage, whereas those with poor activity levels and obesity were most likely to have myocardial damage. Importantly, our results also suggest that recommended physical activity levels might lessen the association between obesity and myocardial damage. Furthermore, the presence of subclinical myocardial damage was significantly and similarly associated with incident HF within each cross-category of physical activity and obesity. The protective association of physical activity against subclinical myocardial damage could have implications for HF risk reduction, particularly among the high-risk group of individuals with excess weight. Subclinical myocardial damage, as reflected by hs-cTnT, is increasingly appreciated as a potent risk factor for the development of HF (6,7). In prior work, The p values for the incidence rate difference between elevated and nonelevated

obesity has been linked to elevated hs-cTnT, and those

high-sensitivity cardiac troponin T (hs-cTnT) within each obesity–physical activity

individuals with both obesity and elevated hs-cTnT

cross-category were <0.001 for all groups. HF = heart failure.

had a 9-fold higher risk of future HF than individuals with normal weight and undetectable hs-cTnT (8). analyses (Online Figure 1), with the highest HF risk among the cross-categories seen for those with obesity and poor activity (HR: 2.55; 95% CI: 2.14 to 3.04). Within each cross-category of physical activity and obesity status, the presence of elevated hs-cTnT was strongly associated with higher incidence rates for HF relative to nonelevated hs-cTnT (Figure 2). Analogously, in multivariable Cox regression analyses, elevated

hs-cTnT

was

strongly associated

with

significantly increased HF risk compared with nonelevated hs-cTnT within each obesity–physical activity cross-category (Online Table 3). A test for an interaction in the association between elevated hs-cTnT and incident HF across the cross-categories was not significant (p for interaction ¼ 0.21). Among those with obesity and poor physical activity (the subgroup with the highest likelihood of myocardial damage), elevated hs-cTnT was associated with a 3-fold higher risk of HF compared with nonelevated hs-cTnT (HR: 3.19; 95% CI: 2.28 to 4.47).

Although a prior study in an elderly population demonstrated an association between greater physical activity and lower hs-cTnT levels (17), there are limited data regarding how combinations of physical activity and obesity influence the likelihood of subclinical myocardial damage. The present study extends prior work by showing a graded inverse association between physical activity and hs-cTnT in a population that includes both middle-aged and elderly adults in the general community. Furthermore, we found a statistically significant interaction between physical activity and obesity on myocardial damage, which indicates that this protective association might be stronger among individuals with obesity, a group at particularly high risk for future HF. In the current study, the association between higher physical activity and a lower likelihood of elevated hs-cTnT was seen even after accounting for traditional CVD mediators but was attenuated after adjustment for additional predictors of HF, including hs-CRP. This suggests the associations of physical

DISCUSSION

inactivity with myocardial damage might be related to pathways beyond the effects of physical activity on

In this analysis of a biracial community-based sample

risk factor levels, which might include decreased

of men and women without a history of CVD at

inflammation (18). The mechanisms by which phys-

baseline,

was

ical activity might lead to less myocardial damage are

subclinical

incompletely understood. Laboratory studies have

myocardial damage, as assessed by elevated hs-cTnT

shown modulatory effects of physical activity on

levels. This association was seen among individuals

several

with and without obesity. Findings were consistent

improved cardiac antioxidant capacity and mito-

across demographic subgroups. When we examined

chondrial respiratory function, ultimately leading to

inversely

we

found

associated

that with

physical chronic

activity

myocellular

defense

mechanisms,

with

Florido et al.

JACC: HEART FAILURE VOL. 5, NO. 5, 2017 MAY 2017:377–84

Physical Activity, Obesity, and hs-cTnT

improved myocardial tolerance to noxious stimuli

this study. As with all observational studies, we

(19,20). Physical activity also has favorable effects on

cannot exclude the presence of residual confounding.

cardiac structure and function (21). Further investi-

Additionally, we cannot exclude possible false posi-

gation will be needed to understand whether these

tive findings resulting from multiple testing in our

and other pathways mediate the association between

multivariable analyses. Nonetheless, our findings

physical inactivity and myocardial damage.

within a large, well-characterized, community-based

CLINICAL

IMPLICATIONS. Our study has several

biracial cohort offer new insights regarding the

important clinical implications. Given the high

interrelationship of physical activity and obesity with

morbidity and mortality associated with HF, as well as

myocardial

its growing prevalence, there is an emerging focus on

generalizable.

the early detection of high-risk individuals, such as those with obesity, who would benefit the most from targeted prevention strategies (13). Given prior data demonstrating a potent association between obesity and incident HF that is unlikely to be addressed solely by controlling adiposity-associated cardiovascular risk factors such as hypertension, diabetes, and dyslipidemia (22), promoting increased physical activity could be a particularly important strategy for HF risk reduction among individuals with obesity. Additionally, a dose-response relationship be-

damage

that

are

likely

broadly

CONCLUSIONS In summary, among middle-aged and older adults without a history of clinical CVD, physical activity was inversely associated with subclinical myocardial damage. Additionally, higher physical activity might lessen the association between obesity and subclinical myocardial damage. These results could have important implications for HF prevention, particularly in people with obesity.

tween physical activity and myocardial damage was

ACKNOWLEDGMENTS The authors thank the staff

observed, with those individuals with American Heart

and participants of the ARIC study for their important

Association–recommended levels of physical activity

contributions.

having a lower likelihood of elevated hs-cTnT than those with poor physical activity. However, only 43%

ADDRESS FOR CORRESPONDENCE: Dr. Elizabeth

of

guideline-

Selvin, Department of Epidemiology, Johns Hopkins

recommended levels of physical activity, and this

Bloomberg School of Public Health, 2024 East

number was even lower among those with obesity

Monument Street, Suite 2-600, Baltimore, Maryland

(33%). Given the strong association of subclinical

21287. E-mail: [email protected].

the

study

population

performed

myocardial damage with incident HF, further studies should explore whether hs-cTnT might be used as a marker of cardiovascular health in association with changes in physical activity. This could be particularly relevant among people with obesity, a group known to have higher levels of subclinical myocardial damage and increased HF risk. The present study does have certain limitations. Usual physical activity levels were assessed by a questionnaire at a single point in time. Self-reported activity levels are likely associated with some misclassification and might not fully capture the cumulative effect of regular physical activity on myocardial damage. Furthermore, we did not have information on fitness in the ARIC study. hs-cTnT was measured from stored blood samples, and degradation over time could have modestly affected the absolute values of hs-cTnT; however, given the high correlations observed in prior validity studies (15), relative measures of association should remain unbiased. The nonconcurrence of physical activity and hs-cTnT measurements is also a limitation, and we cannot establish temporality of the observed associations of physical activity with myocardial damage in

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Obesity and subclinical myocardial damage are important risk factors for heart failure. Physical activity is associated with lower risk of heart failure among both non-obese and obese individuals, through unknown mechanisms. In this analysis of ARIC, we found that physical activity was inversely associated with subclinical myocardial damage. Additionally, higher physical activity might lessen the association between obesity and subclinical myocardial damage. Given the strong association of hs-cTnT and heart failure, the current study supports promotion of physical activity as a key strategy for heart failure prevention, particularly among high-risk subgroups such as people with obesity. TRANSLATIONAL OUTLOOK: Physical activity was inversely associated with subclinical myocardial damage among both nonobese and obese individuals, which could represent a mechanism by which physical activity reduces heart failure risk. Further research is needed to elucidate the mechanisms underlying the association of physical activity and heart failure.

383

384

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Physical Activity, Obesity, and hs-cTnT

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KEY WORDS epidemiology, heart failure, obesity, physical activity, troponin T A PPE NDI X For supplemental tables and figures, please see the online version of this article.